Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. Over the past decade, it has become clear that failure of the pancreatic -cell is the final event causing the transition to overt diabetes, even though obesity and peripheral insulin resistance are the factors leading to pre-diabetes. -cell failure here is defined as loss of both function, i.e. glucose stimulated insulin secretion, and inadequate -cell mass, either by increased apoptosis or a failure to proliferate in response to metabolic demand. While several drugs are in use to reduce insulin resistance and increase insulin secretion, none exist that address -cell failure. In fact, at present, no good targets are known that would allow such drug development. Because the -cell plays such a central role in the pathogenesis of diabetes, and because epigenetic factors (i.e. long term changes in the transcriptional program reflected in chromatin status) are likely to be the predominant consequence of the life-style changes and environmental factors that lead up to diabetes, we will determine the epigenome of both healthy and type 2 diabetic human -cells. This effort will lay the groundwork to defining the pathways and genes that can be targeted in the future for the development of new therapies that address -cell failure. Specifically, we will determine both activating and repressing chromatin marks in -cells isolated from 50 healthy and 50 type 2 diabetic organ donors using ChIP-Seq technology. Secondly, we will analyze the microRNA profile in the same -cell preparations, as miRNAs are strong candidates to modify the transcriptome of the diabetic -cell. Third, we will analyze a novel chromatin mark discovered at Penn that links the stress mediator AMPK to chromatin status. Fourth, we will perform a comprehensive computational biology analysis to identify the nodes and regulatory pathways that are affected in diabetic -cells. PUBLIC HEALTH RELEVANCE: Diabetes mellitus is a lifelong chronic disease with worldwide prevalence estimated at 180 million patients in 2007. Over the past decade, it has become clear that failure of the pancreatic beta-cell, the insulin producing cell, is the final event causing the transition to overt diabetes, even though obesity and peripheral insulin resistance are the factors leading to pre- diabetes. We will determine the epigenetic, that is not mutation based, changes in the genome of the diabetic beta-cell that cause it to fail. This work will identify new potential drug targets for the treatment of type 2 diabetes.